Systematic review: Investigating the prognostic performance of four non-invasive tests in alcohol-related liver disease.

BACKGROUND AND AIM: Mortality of alcohol-related liver disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive tests (NITs) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease, and in particular in ArLD, is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (Fibrosis 4 test [FIB4], Enhanced Liver Fibrosis [ELF] test, FibroScan, and FibroTest) in ArLD. METHODS: Applying systematic review methodology, we searched four databases from inception to May 2020. Inclusion/exclusion criteria were applied to search using Medical Subject Heading terms and keywords. The first and second reviewers independently screened results, extracted data, and performed risk-of-bias assessment using Quality in Prognosis Studies tool. RESULTS: Searches produced 25 088 articles. After initial screening, 1020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4 + FibroScan, and one on FibroTest + FIB4. Area under the receiver operating characteristic curves for outcome prediction ranged from 0.65 to 0.76 for FibroScan, 0.64 to 0.83 for FIB4, 0.69 to 0.79 for FibroTest, and 0.72 to 0.85 for ELF. Studies scored low-moderate risk of bias for most domains but high risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. CONCLUSIONS: This systematic review returned 11 papers, six of which were conference abstracts and one unpublished manuscript. While the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (area under the receiver operating characteristic curves >0.7 in each NIT category) and may add value to prognostication in clinical practice.

[Immune cells role and their new potential therapeutic targets in the pathogenesis of alcoholic liver disease].

The key factors driving the pathogenesis of alcoholic liver disease are still not fully understood. At present, it is believed that the direct toxic effects of ethanol and its intermediate metabolite acetaldehyde can cause oxidative stress, mitochondrial damage, adipogenesis, malnutrition, intestinal endotoxin leakage, etc., thereby participating in the occurrence and progression of alcoholic liver disease. Among the many pathogenic factors that have been revealed, the immunological mechanism plays an important role. Therefore, the role of immune cells and inflammatory mediators has attracted much attention. This article reviews and summarizes the new progress of specific immune cell mechanisms involved in innate and adaptive immune response during the formation and development of alcoholic liver disease, and proposes potential therapeutic targets and clinical trials of related new drugs, which may improve the re-recognition of molecular mechanism and treatment expectation in clinical practice.

[Role of NLRP3 inflammasome in the pathogenesis of alcoholic liver disease].

Chronic excess alcohol intake triggers the formation of enterogenic endotoxemia. TLR4 ligand localization activates nuclear transcription factor NF-κB by inducing the up-regulation of NLRP3 inflammasome and the biologically inactive IL-1ß and IL-18 precursors to form initiation of pro-inflammatory signals. Under the influence of ethanol, the damaged hepatocyte release uric acid, and adenosine triphosphate and induces NLRP3 inflammasome assembly and functional activation in Kupffer cells to promote the release of inflammatory mediators, such as interleukin-1ß and interleukin-18, that cascade mediates inflammation and drive alcoholic liver disease from steatosis to inflammation and fibrosis. The NLRP3 inflammasome acts as a ligand-sensing element and plays an important role in mediating the immune and inflammatory response in the course of alcoholic liver disease. Thus, exploring the activation mechanism of NLRP3 inflammasome and its pathogenic role may provide a new idea in the clinical treatment of alcoholic liver disease.

Coordinated care for patients with cirrhosis: fewer liver-related emergency admissions and improved survival.

OBJECTIVES: To compare the incidence of liver-related emergency admissions and survival of patients after hospitalisation for decompensated cirrhosis at two major hospitals, one applying a coordinated chronic disease management model (U1), the other standard care (U2); to examine predictors of mortality for these patients. DESIGN: Retrospective observational cohort study. SETTING: Two major tertiary hospitals in an Australian capital city. PARTICIPANTS: Patients admitted with a diagnosis of decompensated cirrhosis during October 2013 - October 2014, identified on the basis of International Classification of Diseases (ICD-10) codes. MAIN OUTCOME MEASURES: Incident rates of liver-related emergency admissions; survival (to 3 years). RESULTS: Sixty-nine patients from U1 and 54 from U2 were eligible for inclusion; the median follow-up time was 530 days (range, 21-1105 days). The incidence of liver-related emergency admissions was lower for U1 (mean, 1.14 admissions per person-year; 95% CI, 0.95-1.36) than for U2 (mean, 1.55 admissions per person-year; 95% CI, 1.28-1.85; adjusted incidence rate ratio [U1 v U2], 0.52; 95% CI, 0.28-0.98; P = 0.042). The adjusted probabilities of transplantation-free survival at 3 years were 67.7% (U1) and 37.2% (U2) (P = 0.009). Independent predictors of reduced transplantation-free free survival were Charlson comorbidity index score (per point: hazard ratio [HR], 1.27; 95% CI, 1.05-1.54, P = 0.014), liver-related emergency admissions within 90 days of discharge (HR, 3.60; 95% CI, 1.87-6.92; P < 0.001), and unit (U2 v U1: HR, 2.54, 95% CI, 1.26-5.09; P = 0.009). CONCLUSIONS: A coordinated care model for managing patients with decompensated cirrhosis was associated with improved survival and fewer liver-related emergency admissions than standard care.

Surveillance improves survival of patients with hepatocellular carcinoma: a prospective population-based study.

OBJECTIVES: To determine the factors associated with survival of patients with hepatocellular carcinoma (HCC) and the effect of HCC surveillance on survival. DESIGN, SETTING AND PARTICIPANTS: Prospective population-based cohort study of patients newly diagnosed with HCC in seven tertiary hospitals in Melbourne, 1 July 2012 - 30 June 2013. MAIN OUTCOME MEASURES: Overall survival (maximum follow-up, 24 months); factors associated with HCC surveillance participation and survival. RESULTS: 272 people were diagnosed with incident HCC during the study period; the most common risk factors were hepatitis C virus infection (41%), alcohol-related liver disease (39%), and hepatitis B virus infection (22%). Only 40% of patients participated in HCC surveillance at the time of diagnosis; participation was significantly higher among patients with smaller median tumour size (participants, 2.8 cm; non-participants, 6.0 cm; P < 0.001) and earlier Barcelona Clinic Liver Cancer (BCLC) stage disease (A/B, 59%; C/D, 25%; P < 0.001). Participation was higher among patients with compensated cirrhosis or hepatitis C infections; it was lower among those with alcohol-related liver disease or decompensated liver disease. Median overall survival time was 20.8 months; mean survival time was 18.1 months (95% CI, 16.6-19.6 months). Participation in HCC surveillance was associated with significantly lower mortality (adjusted hazard ratio [aHR], 0.60; 95% CI, 0.38-0.93; P = 0.021), as were curative therapies (aHR, 0.33; 95% CI, 0.19-0.58). Conversely, higher Child-Pugh class, alpha-fetoprotein levels over 400 kU/L, and later BCLC disease stages were each associated with higher mortality. CONCLUSIONS: Survival for patients with HCC is poor, but may be improved by surveillance, associated with the identification of earlier stage tumours, enabling curative therapies to be initiated.

Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice.

BACKGROUND & AIMS: Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. METHODS: Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. RESULTS: Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donor mice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. CONCLUSIONS: Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. LAY SUMMARY: Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of human ALD through intestinal microbiota manipulation.

[Research advances in risk factors for alcoholic liver disease].

Only a small number of people may develop severe alcoholic liver disease after continuous or excessive drinking, which is different from the harm caused by smoking, and some people may even develop alcoholic liver disease associated with inflammation, liver cirrhosis, or primary liver cancer. There are complex risk factors for liver injury in these people; besides ethnic and genetic factors, drinking volume, and drinking duration, more important factors are involved in the pathophysiological changes of the liver, such as the type and quality of alcohol, drinking pattern, socioeconomic status, and government public policy, which may be the determining factors for the development of alcoholic liver disease. On the basis of literature review, this article proposes the concept that "liquor does not equal to alcohol" , which has important guiding significance for healthy drinking and the prevention of alcoholic liver disease.

Alcoholic foamy degeneration: an unusual presentation of the alcoholic liver disease diagnosed on autopsy.

Alcoholic foamy degeneration (AFD) is an uncommon presentation of alcoholic liver disease (ALD) with characteristic histologic findings of foamy-looking hepatocytes due to the presence of abundant microvesicles of fat within the cytoplasm predominantly in perivenular and midzonal regions without inflammation and fibrosis. It is underdiagnosed as the patients quickly recover after alcoholic abstinence and are rarely caught on biopsies. AFD has better prognosis than alcoholic hepatitis, and the injury mechanism is different, warranting a different diagnosis. We present an uncommon case of AFD incidentally diagnosed during autopsy in a chronic alcoholic and diabetic man.

Telomere length in patients with alcohol-associated liver disease: a brief report.

The intact telomere structure is essential for the prevention of the chromosome end-to-end fusions and maintaining genomic integrity. The maintenance of telomere length is critical for cellular homeostasis. The shortening of telomeres has been reported in patients with chronic liver diseases. The telomere length has not been systemically studied in patients with alcohol-associated liver disease (ALD) at different stages, such as alcoholic hepatitis and alcoholic cirrhosis. In this brief report, we observed evidence of telomere shortening without changes in the telomerase activity in the liver of patients with alcoholic hepatitis and alcoholic cirrhosis when compared with controls. The alterations in the genes associated with telomere binding proteins were only observed in patients with alcoholic cirrhosis. Future studies are required to determine the mechanism of how alcohol affects the length of the telomere and if the shortening impacts the disease progression in ALD.

Health and economic burden due to alcohol-associated liver diseases in the Union Territory of Delhi: A Markov probabilistic model approach.

BACKGROUND: Nearly one-fifth of all deaths attributable to alcohol are due to liver diseases. METHODS: The study employs a Markov Probabilistic Modeling approach considering various clinical spectrum of alcohol-associated liver diseases (ALD), to gauge the health and economic burden due to ALD for the national capital territory of Delhi, from March 2017 to February 2018. The health impact was estimated through Disability Adjusted Life Years (DALYs), years of life lost (YLL), and total deaths due to ALD. The economic burden of ALD was assessed assuming the current health-seeking preferences and assuming that all the diseased individuals are cared for in the public health systems. Sensitivity analysis was done by Monte Carlo simulations. RESULTS: Total number of estimated deaths due to ALD in the national capital territory of Delhi for one year period from March 2017 was 8367. The DALYs due to ALD were estimated to be 0.247 million life years; this includes 0.178 million YLL and 0.069 million life years lost due to disability. The total cost of treating ALD was estimated to be 92.94 billion Indian rupees, if patients sought care based on current preferences and 55.52 billion Indian rupees if all diseased individuals were cared for in public health systems. The total excise revenue due to alcohol to the Government is being Indian rupees 43.1 billion in the said year. CONCLUSION: The high burden of ALD in terms of lives lost, DALYs lost, and more than two times higher estimated expense for care than the revenue generation due to alcohol clearly indicates that it would be prudent to initiate social engineering and preventive strategies to lessen the growing burden of ALD in India. The Delhi model for health and economic burden of ALD could help the country develop policies for better health outcomes of these patients.

Alcohol use disorder and liver transplant: new perspectives and critical issues.

Alcoholic liver disease is a consolidated indication for liver transplantation, but many unsolved issues can be highlighted. Patients with alcohol use disorder develop peculiar comorbidities that can become contraindications for transplantation. Moreover, a number of social and psychological patterns should be evaluated to select candidates with a low risk of alcohol relapse and adequate post-transplant adherence. In this context, the 6-month rule is too rigid to be widely applied. A short period of abstinence (1 to 3 months) is useful to estimate recovery of liver function and, possibly to avoid transplant. Cardiovascular disorders and extra-hepatic malignancies represent the main clinical issues after transplant. Patients transplanted due to alcoholic disease are a major risk for other liver diseases. Severe corticosteroid-resistant alcoholic acute hepatitis is a debated indication for transplant. However, available data indicate that well-selected patients have excellent post-transplant outcomes. Behavioral therapy, continued psychological support and a multidisciplinary team are essential to achieve and maintain complete alcohol abstinence during the transplant process. Alcoholic liver disease is an excellent indication for a liver transplant but patients with alcohol use disorder deserve a personalized approach and dedicated resources.

Programmed cell death in alcohol-associated liver disease.

Alcohol-associated liver disease (ALD), which ranges from mild disease to alcohol-associated hepatitis and cirrhosis, is the most prevalent type of chronic liver disease and a leading cause of morbidity and mortality worldwide. Accumulating evidence reveals that programmed cell death (PCD) plays a crucial role in progression of ALD involving crosstalk between hepatocytes and immune cells. Multiple pathways of PCD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis, are reported in ALD. Interestingly, PCD pathways are intimately linked and interdependent, making it difficult to therapeutically target a single pathway. This review clarifies the multiple types of PCD occurring in liver and focuses on crosstalk between hepatocytes and innate immune cells in ALD.

Pathological diagnosis of alcoholic liver disease / 临床肝胆病杂志

Alcoholic liver disease （ALD） is a liver disease caused by long-term heavy drinking. With the improvement in the living standard of Chinese people， the incidence rate of ALD tends to increase significantly. The typical pathological patterns of ALD include alcoholic steatosis， alcoholic steatohepatitis， liver fibrosis， and alcoholic cirrhosis. The diverse and complex pathological morphology of ALD and its similarities with other liver diseases pose a great challenge to pathologists. This article reviews the histopathological morphology， grading and staging systems， and differential diagnosis of ALD.

An excerpt of the American College of Gastroenterology clinical guideline on alcohol-associated liver disease in 2024 / 临床肝胆病杂志

The American College of Gastroenterology published the clinical guideline on alcohol-associated liver disease （ALD） in January 2024 in American Journal of Gastroenterology. This guideline elaborates on the epidemiology and disease burden of ALD and alcohol use disorder， the risk factors for ALD， the diagnosis and treatment of alcohol use disorder， the disease spectrum of ALD， the management of ALD， and public policy and prevention. This article gives an excerpt of the recommendations and key points/statements in this guideline.

Effectiveness of increasing alcohol excise taxes in the management of alcohol-associated liver disease in China / 临床肝胆病杂志

Increasing alcohol excise taxes has been confirmed by the World Health Organization as the most cost-effective public policy for reducing alcohol consumption at the population level. In recent years, studies in foreign countries have believed that increasing alcohol excise taxes can improve the burden of alcohol-associated liver disease (ALD), but it is still unclear whether this policy is applicable to ALD management in China. Therefore, with reference to related research evidence in China and globally, this article analyzes the key factors influencing the effectiveness of the policy of increasing alcohol excise taxes from the perspective of ALD management in China, including tax shifting, price elasticity of demand, and unrecorded alcohol, and introduces other public policies that help curb ALD. We think that increasing alcohol excise taxes is currently a useful but not effective policy for improving the burden of ALD in China.

Alcoholic foamy degeneration: an unusual presentation of the alcoholic liver disease diagnosed on autopsy

ABSTRACT Alcoholic foamy degeneration (AFD) is an uncommon presentation of alcoholic liver disease (ALD) with characteristic histologic findings of foamy-looking hepatocytes due to the presence of abundant microvesicles of fat within the cytoplasm predominantly in perivenular and midzonal regions without inflammation and fibrosis. It is underdiagnosed as the patients quickly recover after alcoholic abstinence and are rarely caught on biopsies. AFD has better prognosis than alcoholic hepatitis, and the injury mechanism is different, warranting a different diagnosis. We present an uncommon case of AFD incidentally diagnosed during autopsy in a chronic alcoholic and diabetic man.

Ursolic acid in / 临床肝胆病杂志

Objective To investigate the inhibitory effect of ursolic acid in Hippophae rhamnoides L. on hepatocyte apoptosis in rats with alcoholic liver disease based on the mitochondria-cytochrome c pathway. Methods A total of 50 specific pathogen-free male Wistar rats were divided into normal control group, alcohol model group, and low-, middle-, and high-dose ursolic acid groups using a random number table, with 10 rats in each group. The rats in the normal control group were given normal saline by gavage once a day for 8 weeks; the rats in the alcohol model group were given alcohol at increasing concentrations by gavage for 8 consecutive weeks; the rats in the low-, middle-, and high-dose ursolic acid groups were given ursolic acid at a dose of 50, 100, and 150 mg/kg, respectively, followed by an equal volume of alcohol as the model group 1 hour later. Serum liver function parameters were measured for each group; HE staining was used to observe liver histopathology; an electron microscope was used to observe hepatocyte ultrastructure; the TUNEL method was used to measure hepatocyte apoptosis; Western Blotting was used to measure the protein expression levels of cytochrome c and activated caspase-3 in hepatocyte mitochondria and cytoplasm. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. Results Compared with the alcohol model group, the middle- and high-dose ursolic acid groups had significant reductions in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase (all P < 0.05). The rats in the alcohol model group had disordered arrangement of hepatic cords with marked hepatocyte edema and fatty degeneration, while those in the middle- and high- dose ursolic acid groups had basically normal arrangement of hepatic cords and a significant improvement in hepatocyte fatty degeneration, as well as a significant increase in the number of hepatocyte mitochondria and a significant improvement in morphology. Compared with the alcohol model group, the middle- and high-dose ursolic acid groups had significantly lower hepatocyte apoptosis rate and protein expression levels of cytochrome c and caspase-3 in cytoplasm (all P < 0.05). Conclusion Ursolic acid in Hippophae rhamnoides L. can improve the liver function and histomorphology of rats with alcoholic liver disease, possibly by inhibiting the release of cytochrome c in hepatocyte mitochondria, the activation of caspase-3, and the apoptosis of hepatocytes via the mitochondria-cytochrome c pathway.

Research advances in the role of / 临床肝胆病杂志

Alcoholic liver disease (ALD) is one of the most common chronic liver diseases worldwide and includes the different stages of steatosis, steatohepatitis, fibrosis, and liver cirrhosis. Enterococcus faecalis is a common bacterium for nosocomial infection and has a significant impact on the prognosis of patients with alcoholic hepatitis. This review mainly introduces the pathogenesis of ALD and the pathogenic mechanism of E. faecalis , summarizes the research advances in E. faecalis in ALD, and briefly describes the detection and treatment methods for E. faecalis infection in clinical practice. Since there is an extremely high mortality rate in ALD patients with lytic E. faecalis infection, an in-depth understanding of E. faecalis has become an important issue nowadays.